Neuroinvasive West Nile Virus Infection in Immunosuppressed and Immunocompetent Adults.

Importance: West Nile virus (WNV) is the leading cause of human arboviral disease in the US, peaking during summer. The incidence of WNV, including its neuroinvasive form (NWNV), is increasing, largely due to the expanding distribution of its vector, the Culex mosquito, and climatic changes causing heavy monsoon rains. However, the distinct characteristics and outcomes of NWNV in individuals who are immunosuppressed (IS) and individuals who are not IS remain underexplored. Objective: To describe and compare clinical and radiographic features, treatment responses, and outcomes of NWNV infection in individuals who are IS and those who are not IS. Design, Setting, and Participants: This retrospective cohort study used data from the Mayo Clinic Hospital system collected from July 2006 to December 2021. Participants were adult patients (age ≥18 years) with established diagnosis of NWNV infection. Data were analyzed from May 12, 2020, to July 20, 2023. Exposure: Immunosuppresion. Main Outcomes and Measures: Outcomes of interest were clinical and radiographic features and 90-day mortality among patients with and without IS. Results: Of 115 participants with NWNV infection (mean [SD] age, 64 [16] years; 75 [66%] male) enrolled, 72 (63%) were not IS and 43 (37%) were IS. Neurologic manifestations were meningoencephalitis (98 patients [85%]), encephalitis (10 patients [9%]), and myeloradiculitis (7 patients [6%]). Patients without IS, compared with those with IS, more frequently reported headache (45 patients [63%] vs 18 patients [42%]) and myalgias (32 patients [44%] vs 9 patients [21%]). In contrast, patients with IS, compared with those without, had higher rates of altered mental status (33 patients [77%] vs 41 patients [57%]) and myoclonus (8 patients [19%] vs 8 patients [4%]). Magnetic resonance imaging revealed more frequent thalamic T2 fluid-attenuated inversion recovery hyperintensities in individuals with IS than those without (4 patients [11%] vs 0 patients). Individuals with IS had more severe disease requiring higher rates of intensive care unit admission (26 patients [61%] vs 24 patients [33%]) and mechanical ventilation (24 patients [56%] vs 22 patients [31%]). The 90-day all-cause mortality rate was higher in the patients with IS compared with patients without IS (12 patients [28%] vs 5 patients [7%]), and this difference in mortality persisted after adjusting for Glasgow Coma Scale score (adjusted hazard ratio, 2.22; 95% CI, 1.07-4.27; P = .03). Individuals with IS were more likely to receive intravenous immunoglobulin than individuals without IS (12 individuals [17%] vs 24 individuals [56%]), but its use was not associated with survival (hazard ratio, 1.24; 95% CI, 0.50-3.09; P = .64). Conclusions and Relevance: In this cohort study of individuals with NWNV infection, individuals with IS had a higher risk of disease complications and poor outcomes than individuals without IS, highlighting the need for innovative and effective therapies to improve outcomes in this high-risk population.

Identifying and Addressing Barriers to Systemic Thrombolysis for Acute Ischemic Stroke in the Inpatient Setting: A Quality Improvement Initiative.

OBJECTIVES: To identify barriers to inpatient alteplase administration and implement an interdisciplinary program to reduce time to systemic thrombolysis. PATIENTS AND METHODS: Compared with patients presenting to the emergency department with an acute ischemic stroke (AIS), inpatients are delayed in receiving alteplase for systemic thrombolysis. Institutional AIS metrics were extracted from the electronic medical records of patients presenting as an inpatient stroke alert. All patients who received alteplase for AIS were included in the analysis. A gap analysis was used to assess institutional deficiencies. An interdisciplinary intervention was initiated to address these deficiencies. Efficacy was measured with pre- and postintervention surveys and institutional AIS metric analysis. Statistical significance was determined using the Student t test. We identified 5 patients (mean age, 73 years; 100% (5/5) male; 80% (4/5) white) who met inclusion criteria for the preintervention period (January 1, 2017, to December 31, 2017) and 10 patients (mean age, 71 years; 50% male; 80% white) for the postintervention period (October 31, 2018, to July 1, 2020). RESULTS: We found barriers to rapid delivery of thrombolytic treatment to include alteplase availability and comfort with bedside reconstitution. Interdisciplinary intervention strategies consisted of stocking alteplase on additional floors as well as structured education and hands-on alteplase reconstitution simulations for resident physicians. The mean time from stroke alert to thrombolysis was shorter postintervention than preintervention (57.4 minutes vs 77.8 minutes; P=.03). CONCLUSION: A coordinated interdisciplinary approach is effective in reducing time to systemic thrombolysis in patients experiencing AIS in the inpatient setting. A similar program could be implemented at other institutions to improve AIS treatment.

Calcitonin Gene-Related Peptide Antagonists for the Prevention of Migraine: Highlights From Pivotal Studies and the Clinical Relevance of This New Drug Class.

Objective: To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. Data Sources: A literature search was performed in PubMed (January 2009 to November 2019) using the terms migraine, calcitonin gene-related peptide (CGRP), erenumab, fremanezumab, and galcanezumab for clinical trials and studies. Study Selection and Data Extraction: Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. Data Synthesis: In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. Relevance to Patient Care and Clinical Practice: This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Conclusions: Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.

Nonconvulsive status epilepticus secondary to acute porphyria crisis.

Both variegate and acute intermittent porphyria can manifest with various neurological symptoms. Although acute symptomatic seizures have been previously described, they are typically tonic-clonic and focal impaired awareness seizures. Convulsive status epilepticus and epilepsia partialis continua are rare and have been described on a case report basis. To our knowledge, there are no previously reported cases describing non-convulsive status epilepticus (NCSE) with electroencephalogram (EEG) documentation in the setting of acute porphyria crisis. We report a unique presentation of NCSE, which resolved after administering levetiracetam in a patient with variegate porphyria, without a known seizure disorder.

Admission Systolic Blood Pressure Predicts the Number of Blood Pressure Medications at Discharge in Patients With Primary Intracerebral Hemorrhage.

BACKGROUND: Control of systolic blood pressure (SBP) after primary intracerebral hemorrhage improves outcomes. Factors determining the number of blood pressure medications (BPM) required for goal SBP<160 mm Hg at discharge are unknown. We hypothesized that higher admission-SBPs require a greater number of BPM for goal discharge-SBP<160 mm Hg, and investigated factors influencing this goal. MATERIALS AND METHODS: We conducted a retrospective review of 288 patients who presented with primary intracerebral hemorrhage. Admission-SBP was obtained. Primary outcome was the number of BPM at discharge. Comparison was made between patients presenting with and without a history of hypertension, and patients discharged on <3 and ≥3 BPM. RESULTS: Patients with hypertension history had a higher median admission-SBP compared with those without (180 vs. 157 mm Hg, P=0.0001). In total, 133 of 288 (46.2%) patients were discharged on <3 BPM; 155/288 (53.8%) were discharged on ≥3 BPM. Hypertension history (P<0.0001) and admission-SBP (P<0.0001) predicted the number of BPM at discharge. In patients without hypertension history, every 10 mm Hg increase in SBP resulted in an absolute increase of 0.5 BPM at discharge (P=0.0011), whereas in those with hypertension, the absolute increase was 1.3 BPM (P=0.0012). In comparison with patients discharged on <3 BPM, patients discharged on ≥3 BPM were more likely to have a higher median admission-SBP, be younger in age, belong to the African-American race, have a history of diabetes, have higher median admission-National Institutes of Health Stroke Scale and modified Rankin Scale of 4 to 5 at discharge. CONCLUSIONS: An understanding of the factors influencing BPM at discharge may help clinicians better optimize blood pressure control both before and after discharge.

Relevance of the Updated Food and Drug Administration Alteplase Label for Acute Ischemic Stroke: The Estimated Impact and Current Guidelines.

In 2015, the Food and Drug Administration updated the contraindications for the use of alteplase in acute ischemic stroke (AIS), potentially creating a greater impact on treatment. A history of intracranial hemorrhage and recent stroke within 3 months were removed as contraindications, increasing the number of patients eligible for alteplase. The aim of this commentary is to call attention to the updates and discuss them relative to current American Heart Association/American Stroke Association guidelines. Additionally, we estimate the clinical impact of the updates by analyzing AIS admissions to a large-volume Comprehensive Stroke Center.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

BACKGROUND: Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. OBJECTIVE: To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. METHODS: Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. RESULTS: We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. CONCLUSIONS: Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Systemic Inflammatory Response Syndrome and Outcomes in Intracerebral Hemorrhage.

BACKGROUND: To identify the patients at greatest odds for systemic inflammatory response syndrome (SIRS) and examine the association between SIRS and outcomes in patients presenting with intracerebral hemorrhage (ICH). METHODS: We retrospectively reviewed consecutive patients presenting to a tertiary care center from 2008 to 2013 with ICH. SIRS was defined according to standard criteria as 2 or more of the following: (1) body temperature <36 or >38 °C, (2) heart rate >90 beats per minute, (3) respiratory rate >20, or (4) white blood cell count <4000/mm(3) or >12,000/mm(3) or >10 % polymorphonuclear leukocytes for >24 h in the absence of infection. The outcomes of interest, discharge modified Rankin Scale (mRS 4-6), death, and poor discharge disposition (discharge anywhere but home or inpatient rehab) were assessed using logistic regression. RESULTS: A total of 249 ICH patients met inclusion criteria and 53 (21.3 %) developed SIRS during their hospital stay. A score was developed (ranging from 0 to 3) to identify patients at greatest risk for developing SIRS. Adjusting for stroke severity, SIRS was associated with mRS 4-6 (OR 5.25, 95 %CI 2.09-13.2) and poor discharge disposition (OR 3.74, 95 %CI 1.58-4.83) but was not significantly associated with death (OR 1.75, 95 %CI 0.58-5.32). We found that 33 % of the effect of ICH score on poor functional outcome at discharge was explained by the development of SIRS in the hospital (Sobel 2.11, p = 0.03). CONCLUSION: We observed that approximately 20 % of patients with ICH develop SIRS, and that patients with SIRS were at increased risk of having poor functional outcome at discharge.

Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry.

BACKGROUND: There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention. METHODS: Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology. RESULTS: A total of 78 AF patients (mean age 71 ± 9years; 54% men; 81% IS, 19% TIA; median CHADS2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2-5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 ± 5 months (range 1-18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria (n = 1) and rectal bleeding (n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%). DISCUSSION: Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation.

A case of Brugada syndrome presenting with incessant polymorphic ventricular tachycardia.

Brugada syndrome, an inherited arrhythmogenic cardiac disease, manifests with ST-segment changes in the right precordial leads, right bundle block pattern, and susceptibility to ventricular tachyarrhythmias and sudden death. The only established therapy for this disease is prevention of sudden death by implantation of a defibrillator. Herein we describe a case of a patient who presented with incessant ventricular tachycardia (VT) and syncope and who had a type 1 Brugada pattern on ECG. The patient was successfully treated with quinidine, after which the classically described type 2 and 3 patterns emerged.

Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation.

Initiation of Na(+)-glucose cotransport in intestinal absorptive epithelia causes NHE3 to be translocated to the apical plasma membrane, leading to cytoplasmic alkalinization. We reported recently that this NHE3 translocation requires ezrin phosphorylation. However, the kinase that phosphorylates ezrin in this process has not been identified. Because Akt has also been implicated in NHE3 translocation, we investigated the hypothesis that Akt phosphorylates ezrin. After initiation of Na(+)-glucose cotransport, Akt is activated with kinetics that parallel those of ezrin phosphorylation. Inhibition of p38 MAP kinase, which blocks ezrin phosphorylation, also prevents Akt activation. Purified Akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an ATP-dependent manner. This in vitro phosphorylation can be prevented by Akt inhibitors. In intact cells, inhibition of either phosphoinositide 3-kinase, an upstream regulator of Akt, or inhibition of Akt itself using inhibitors validated in vitro prevents ezrin phosphorylation after initiation of Na(+)-glucose cotransport. Specific small interfering RNA knockdown of Akt2 prevented ezrin phosphorylation in intact cells. Pharmacological Akt inhibition or Akt2 knockdown also prevented NHE3 translocation and activation after initiation of Na(+)-glucose cotransport, confirming the functional role of Akt2. These studies therefore identify Akt2 as a critical kinase that regulates ezrin phosphorylation and activation. This Akt2-dependent ezrin phosphorylation leads to NHE3 translocation and activation.

Ezrin regulates NHE3 translocation and activation after Na+-glucose cotransport.

Initiation of Na(+)-glucose cotransport in intestinal epithelial cells leads to activation of the apical Na(+)-H(+) exchanger NHE3 and subsequent increases in cytoplasmic pH (pH(i)). This process requires activation of p38 mitogen-activated protein (MAP) kinase, but additional signaling intermediates have not been identified. One candidate is the cytoskeletal linker protein ezrin, which interacts with NHE3 via specific regulatory proteins. The data show that initiation of Na(+)-glucose cotransport resulted in rapid increases in both apical membrane-associated NHE3 and cytoskeletal-associated ezrin and occurred in parallel with ezrin phosphorylation at threonine 567. Phosphorylation at this site is known to activate ezrin and increase its association with actin. Consistent with a central role for ezrin activation in this NHE3 regulation, an N-terminal dominant negative ezrin construct inhibited both NHE3 recruitment and pH(i) increases after Na(+)-glucose cotransport. Ezrin phosphorylation occurred in parallel with p38 MAP kinase activation, and the latter proceeded normally in cells expressing dominant negative ezrin. In contrast, inhibition of p38 MAP kinase prevented increases in ezrin phosphorylation after initiation of Na(+)-glucose cotransport. Thus, ezrin phosphorylation after Na(+)-glucose cotransport requires p38 MAP kinase activity, but p38 MAP kinase activation does not require ezrin function. These data describe a specific role for ezrin in the coordinate regulation of Na(+)-glucose cotransport and Na(+)-H(+) exchange. Intact ezrin function is necessary for NHE3 recruitment to the apical membrane and NHE3-dependent pH(i) increases triggered by Na(+)-glucose cotransport. The data also define a pathway of p38 MAP kinase-dependent ezrin activation.

Increased dietary protein modifies glucose and insulin homeostasis in adult women during weight loss.

Amino acids interact with glucose metabolism both as carbon substrates and by recycling glucose carbon via alanine and glutamine; however, the effect of protein intake on glucose homeostasis during weight loss remains unknown. This study tests the hypothesis that a moderate increase in dietary protein with a corresponding reduction of carbohydrates (CHO) stabilizes fasting and postprandial blood glucose and insulin during weight loss. Adult women (n = 24; >15% above ideal body weight) were assigned to either a Protein Group [protein: 1.6 g/(kg. d); CHO <40% of energy] or CHO Group [protein: 0.8 g/(kg. d); CHO >55%]. Diets were equal in energy (7100 kJ/d) and fat (50 g/d). After 10 wk, the Protein Group lost 7.53 +/- 1.44 kg and the CHO Group lost 6.96 +/- 1.36 kg. Plasma amino acids, glucose and insulin were determined after a 12-h fast and 2 h after a 1.67 MJ test meal containing either 39 g CHO, 33 g protein and 13 g fat (Protein Group) or 57 g CHO, 12 g protein and 14 g fat (CHO Group). After 10 wk, subjects in the CHO Group had lower fasting (4.34 +/- 0.10 vs 4.89 +/- 0.11 mmol/L) and postprandial blood glucose (3.77 +/- 0.14 vs. 4.33 +/- 0.15 mmol/L) and an elevated insulin response to meals (207 +/- 21 vs. 75 +/- 18 pmol/L). This study demonstrates that consumption of a diet with increased protein and a reduced CHO/protein ratio stabilizes blood glucose during nonabsorptive periods and reduces the postprandial insulin response.

A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women.

Claims about the merits or risks of carbohydrate (CHO) vs. protein for weight loss diets are extensive, yet the ideal ratio of dietary carbohydrate to protein for adult health and weight management remains unknown. This study examined the efficacy of two weight loss diets with modified CHO/protein ratios to change body composition and blood lipids in adult women. Women (n = 24; 45 to 56 y old) with body mass indices >26 kg/m(2) were assigned to either a CHO Group consuming a diet with a CHO/protein ratio of 3.5 (68 g protein/d) or a Protein Group with a ratio of 1.4 (125 g protein/d). Diets were isoenergetic, providing 7100 kJ/d, and similar amounts of fat ( approximately 50 g/d). After consuming the diets for 10 wk, the CHO Group lost 6.96 +/- 1.36 kg body weight and the Protein Group lost 7.53 +/- 1.44 kg. Weight loss in the Protein Group was partitioned to a significantly higher loss of fat/lean (6.3 +/- 1.2 g/g) compared with the CHO Group (3.8 +/- 0.9). Both groups had significant reductions in serum cholesterol ( approximately 10%), whereas the Protein Group also had significant reductions in triacylglycerols (TAG) (21%) and the ratio of TAG/HDL cholesterol (23%). Women in the CHO Group had higher insulin responses to meals and postprandial hypoglycemia, whereas women in the Protein Group reported greater satiety. This study demonstrates that increasing the proportion of protein to carbohydrate in the diet of adult women has positive effects on body composition, blood lipids, glucose homeostasis and satiety during weight loss.